Antibody–Cytotoxic Compound Conjugates for Oncology

  • Carol A. Vater
  • Victor S. Goldmacher
Part of the Macromolecular Anticancer Therapeutics book series (CDD&D)


The original rationale underlying the development of antibody–cytotoxic compound conjugates (ACC) was to improve the selectivity of cytotoxic anti-cancer drugs by targeting them to tumors with the help of antibodies. The ACC concept has since matured significantly, following several key advancements: (i) generation of technologies for creating humanized and fully human monoclonal antibodies; (ii) development of conjugatable cytotoxic compounds of sufficient potency to be effective in eradicating tumor cells in an antigen-selective manner; (iii) advances in knowledge and antibody engineering to maximize anti-tumor cell effect or functions; and (iv) optimization of linkers used to conjugate cytotoxic compounds to antibodies in order to achieve both maximal stability of the ACC in the circulation and maximal release of the active cytotoxic component within targeted tumor cells. In this chapter we will focus on our present understanding of what makes an effective ACC for the treatment of oncology patients. We will discuss parameters that are important for the selection of antigen targets, antibodies, cytotoxic compounds, and linkers, and current approaches being taken to further improve the efficacy of ACCs. In addition, we will review preclinical and clinical experiences with the current generation of ACCs.


Cancer Stem Cell Antigen Expression Target Antigen Anaplastic Large Cell Lymphoma Gemtuzumab Ozogamicin 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.



Antibody–cytotoxic compound conjugate


Antibody–drug conjugate


Antibody-dependent cellular cytotoxicity


Acute myelogenous leukemia


Complement-dependent cytotoxicity


Complementarity determining region


Complete response


Cancer stem cell


N-methyl-N-[3-mercapto-1-oxopropyl]-l-alanine ester of maytansinol


N-methyl-N-[4-mercapto-4-methyl-1-oxopentyl]-l-alanine ester of maytansinol


neonatal Fc receptor


IgG Fc receptor


US Food and Drug Administration




Multi-drug resistance


Minor groove-binding alkylating agent


monomethylauristatin E


monomethylauristatin F


Maximum tolerated dose


Partial response


Prostate-specific membrane antigen


Stable disease





We thank our colleagues, Robert Lutz, John Lambert, Rajeeva Singh, Peter Park, Daniel Tavares, Ravi Chari, Yelena Kovtun, and Carol Hausner for critical reading of the manuscript and Yelena Kovtun for drawing the figures.


  1. 1.
    Carter, P. J., P. D. Senter (2008). “Antibody-drug conjugates for cancer therapy.” Cancer J 14(3): 154–69.PubMedCrossRefGoogle Scholar
  2. 2.
    Chari, R. V. (1998). “Targeted delivery of chemotherapeutics: tumor-activated prodrug therapy.” Adv Drug Deliv Rev 31(1–2): 89–104.PubMedCrossRefGoogle Scholar
  3. 3.
    Goldmacher, V. S., W. A. Blattler, J. M., Lambert, R. V. J. Chari (2002). Immunotoxins and antibody-drug conjugates for cancer treatment. Biomedical Aspects of Drug Targeting. V. Muzykantov and V. Torchilin (eds.). Boston/Dordrecht/London, Kluwer Academic Publishers: 291–309.Google Scholar
  4. 4.
    Lambert, J. M. (2005). “Drug-conjugated monoclonal antibodies for the treatment of cancer.” Curr Opin Pharmacol 5(5): 543–9.PubMedCrossRefGoogle Scholar
  5. 5.
    Pastan, I., R. Hassan, et al. (2007). “Immunotoxin treatment of cancer.” Annu Rev Med 58: 221–37.PubMedCrossRefGoogle Scholar
  6. 6.
    Payne, G. (2003). “Progress in immunoconjugate cancer therapeutics.” Cancer Cell 3(3): 207–12.PubMedCrossRefGoogle Scholar
  7. 7.
    Chari, R. V. (2008). “Targeted cancer therapy: conferring specificity to cytotoxic drugs.” Acc Chem Res 41(1): 98–107.PubMedCrossRefGoogle Scholar
  8. 8.
    Schrama, D., R. A. Reisfeld, et al. (2006). “Antibody targeted drugs as cancer therapeutics.” Nat Rev Drug Discov 5(2): 147–59.PubMedCrossRefGoogle Scholar
  9. 9.
    Lee, M. D., T. M. Dunne, M. M. Siegel, C. C. Chang, G. O., Morton, D. B. Borders (1987). “Calicheamicins, a novel family of antitumor antibiotics. I. Chemistry and partial structure of calicheamicin g1.” J Am Chem Soc 109: 3463–3466.Google Scholar
  10. 10.
    Smith, A. L., K. C. Nicolaou (1996). The enediyne antibiotics. J Med Chem 39: 2103–17.PubMedCrossRefGoogle Scholar
  11. 11.
    Zein, N., A. M. Sinha, et al. (1988). “Calicheamicin gamma 1I: an antitumor antibiotic that cleaves double-stranded DNA site specifically.” Science 240(4856): 1198–201.PubMedCrossRefGoogle Scholar
  12. 12.
    Chari, R. V., K. A. Jackel, et al. (1995). “Enhancement of the selectivity and antitumor efficacy of a CC-1065 analogue through immunoconjugate formation.” Cancer Res 55(18): 4079–84.PubMedGoogle Scholar
  13. 13.
    Chari, R. V., B. A. Martell, et al. (1992). “Immunoconjugates containing novel maytansinoids: promising anticancer drugs.” Cancer Res 52(1): 127–31.PubMedGoogle Scholar
  14. 14.
    Kupchan, S. M., Y. Komoda, et al. (1977). “The maytansinoids. Isolation, structural elucidation, and chemical interrelation of novel ansa macrolides.” J Org Chem 42(14): 2349–57.PubMedCrossRefGoogle Scholar
  15. 15.
    Kupchan, S. M., Y. Komoda, et al. (1972). “Maytansine, a novel antileukemic ansa macrolide from Maytenus ovatus.” J Am Chem Soc 94(4): 1354–6.PubMedCrossRefGoogle Scholar
  16. 16.
    Remillard, S., L. I. Rebhun, et al. (1975). “Antimitotic activity of the potent tumor inhibitor maytansine.” Science 189(4207): 1002–5.PubMedCrossRefGoogle Scholar
  17. 17.
    Doronina, S. O., B. A. Mendelsohn, et al. (2006). “Enhanced activity of monomethylauristatin F through monoclonal antibody delivery: effects of linker technology on efficacy and toxicity.” Bioconjug Chem 17(1): 114–24.PubMedCrossRefGoogle Scholar
  18. 18.
    Doronina, S. O., B. E. Toki, et al. (2003). “Development of potent monoclonal antibody auristatin conjugates for cancer therapy.” Nat Biotechnol 21(7): 778–84.PubMedCrossRefGoogle Scholar
  19. 19.
    Almagro, J. C., J. Fransson (2008). “Humanization of antibodies.” Front Biosci 13: 1619–33.PubMedGoogle Scholar
  20. 20.
    Carter, P. J. (2006). “Potent antibody therapeutics by design.” Nat Rev Immunol 6(5):343–57.PubMedCrossRefGoogle Scholar
  21. 21.
    Lonberg, N. (2005). “Human antibodies from transgenic animals.” Nat Biotechnol 23(9): 1117–25.PubMedCrossRefGoogle Scholar
  22. 22.
    Singh R., H. Erickson (2009). Antibody-cytotoxic agent conjugates: preparation and characterization. Methods Mol Biol 525: 445–67.Google Scholar
  23. 23.
    Bross, P. F., J. Beitz, et al. (2001). “Approval summary: gemtuzumab ozogamicin in relapsed acute myeloid leukemia.” Clin Cancer Res 7(6): 1490–6.PubMedGoogle Scholar
  24. 24.
    Beeram, M., H. A. Burris, S. Modi, M. Birkner, S. Girish, J. Tibbitts, S. N. Holden, S. G. Lutzker, I. E. Krop (2008). “A Phase I study of Trastuzumab-DM1, a first-in-class HER2 antibody-drug conjugate (ADC), given every 3 weeks to patients with HER2+ metastatic breast cancer.” American Society of Clinical Oncology Annual Meeting Proceedings: Abstract #1028.Google Scholar
  25. 25.
    Burris, H. A., S. Vukelja, H. S. Rugo, C. Vogel, R. Borson, E. Tan-Chiu, M. Birkner, S. N. Holden, S. Girish, B. Klencke, J. O’Shaughnessy (2008). “A Phase II study of Trastuzumab-DM1 (T-DM1), a HER2 antibody-drug conjugate, in patients with HER2-positive metastatic breast cancer.” ASCO Breast Cancer Symposium Proceedings: Abstract #155.Google Scholar
  26. 26.
    Holden, S. N., M. Beeram, I. E. Krop, H. A. Burris, M Birkner, S Girish, J Tibbitts, S. G Lutzker, S. Modi (2008). “A Phase I study of weekly dosing of Trastuzumab-DM1 (T-DM1) in patients with advanced HER2+ breast cancer.” American Society of Clinical Oncology Annual Meeting Proceedings: Abstract #1029.Google Scholar
  27. 27.
    Younes, A., A. Forero-Torres, N. L. Bartlett, J. P. Leonard, B. Rege, D. A. Kennedy, J. M. Lorenz, E. L. Sievers (2008). “Objective responses in a Phase I dose-escalation study of SGN-35, a novel antibody-drug conjugate (ADC) targeting CD30, in patients with relapsed or refractory Hodgkin lymphoma.” American Society of Clinical Oncology Annual Meeting Proceedings: 8526.Google Scholar
  28. 28.
    Pastan, I., R. Hassan, et al. (2006). “Immunotoxin therapy of cancer.” Nat Rev Cancer 6(7): 559–65.PubMedCrossRefGoogle Scholar
  29. 29.
    Polakis, P. (2005). “Arming antibodies for cancer therapy.” Curr Opin Pharmacol 5(4): 382–7.PubMedCrossRefGoogle Scholar
  30. 30.
    Ricart, A. D., A. W. Tolcher (2007). “Technology insight: cytotoxic drug immunoconjugates for cancer therapy.” Nat Clin Pract Oncol 4(4): 245–55.PubMedCrossRefGoogle Scholar
  31. 31.
    Senter, P. D., C. J. Springer (2001). “Selective activation of anticancer prodrugs by monoclonal antibody-enzyme conjugates.” Adv Drug Deliv Rev 53(3): 247–64.PubMedCrossRefGoogle Scholar
  32. 32.
    Carter, P., L. Smith, et al. (2004). “Identification and validation of cell surface antigens for antibody targeting in oncology.” Endocr Relat Cancer 11(4): 659–87.PubMedCrossRefGoogle Scholar
  33. 33.
    Xie, H., W. A. Blattler (2006). “In vivo behaviour of antibody-drug conjugates for the targeted treatment of cancer.” Expert Opin Biol Ther 6(3): 281–91.PubMedCrossRefGoogle Scholar
  34. 34.
    Kononen, J., L. Bubendorf, et al. (1998). “Tissue microarrays for high-throughput molecular profiling of tumor specimens.” Nat Med 4(7): 844–7.PubMedCrossRefGoogle Scholar
  35. 35.
    Baeckstrom, D., G. C. Hansson, et al. (1991). “Purification and characterization of a membrane-bound and a secreted mucin-type glycoprotein carrying the carcinoma-associated sialyl-Lea epitope on distinct core proteins.” J Biol Chem 266(32): 21537–47.PubMedGoogle Scholar
  36. 36.
    Blumenthal, R. D., E. Leon, et al. (2007). “Expression patterns of CEACAM5 and CEACAM6 in primary and metastatic cancers.” BMC Cancer 7: 2.PubMedCrossRefGoogle Scholar
  37. 37.
    Carrigan C., S. W., Payne G. (2007). “huC242 recognizes a carbohydrate epitope on the CD44 antigen.” Keystone Conference Proceedings: Abstract #107.Google Scholar
  38. 38.
    Hakomori, S. (2001). “Tumor-associated carbohydrate antigens defining tumor malignancy: basis for development of anti-cancer vaccines.” Adv Exp Med Biol 491: 369–402.PubMedGoogle Scholar
  39. 39.
    Johansson, C., O. Nilsson, et al. (1991). “Novel epitopes on the CA50-carrying antigen: chemical and immunochemical studies.” Tumour Biol 12(3): 159–70.PubMedCrossRefGoogle Scholar
  40. 40.
    Pukel, C. S., K. O. Lloyd, et al. (1982). “GD3, a prominent ganglioside of human melanoma. Detection and characterisation by mouse monoclonal antibody.” J Exp Med 155(4): 1133–47.PubMedCrossRefGoogle Scholar
  41. 41.
    Schietinger, A., M. Philip, et al. (2006). “A mutant chaperone converts a wild-type protein into a tumor-specific antigen.” Science 314(5797): 304–8.PubMedCrossRefGoogle Scholar
  42. 42.
    Yin, B. W., K. O. Lloyd (2001). “Molecular cloning of the CA125 ovarian cancer antigen: identification as a new mucin, MUC16.” J Biol Chem 276(29): 27371–5.PubMedCrossRefGoogle Scholar
  43. 43.
    Kovtun, Y. V., C. A. Audette, et al. (2006). “Antibody-drug conjugates designed to eradicate tumors with homogeneous and heterogeneous expression of the target antigen.” Cancer Res 66(6): 3214–21.PubMedCrossRefGoogle Scholar
  44. 44.
    Liu, C., B. M. Tadayoni, et al. (1996). “Eradication of large colon tumor xenografts by targeted delivery of maytansinoids.” Proc Natl Acad Sci U S A 93(16): 8618–23.PubMedCrossRefGoogle Scholar
  45. 45.
    Carmeliet, P., R. K. Jain (2000). “Angiogenesis in cancer and other diseases.” Nature 407(6801): 249–57.PubMedCrossRefGoogle Scholar
  46. 46.
    Minchinton, A. I., I. F. Tannock (2006). “Drug penetration in solid tumours.” Nat Rev Cancer 6(8): 583–92.PubMedCrossRefGoogle Scholar
  47. 47.
    Thurber, G. M., M. M. Schmidt, et al. (2008). “Factors determining antibody distribution in tumors.” Trends Pharmacol Sci 29(2): 57–61.PubMedGoogle Scholar
  48. 48.
    Helft, P. R., R. L. Schilsky, et al. (2004). “A phase I study of cantuzumab mertansine administered as a single intravenous infusion once weekly in patients with advanced solid tumors.” Clin Cancer Res 10(13): 4363–8.PubMedCrossRefGoogle Scholar
  49. 49.
    Bhaskar, V., D. A. Law, et al. (2003). “E-selectin up-regulation allows for targeted drug delivery in prostate cancer.” Cancer Res 63(19): 6387–94.PubMedGoogle Scholar
  50. 50.
    Walter, R. B., B. W. Raden, et al. (2005). “Influence of CD33 expression levels and ITIM-dependent internalization on gemtuzumab ozogamicin-induced cytotoxicity.” Blood 105(3): 1295–302.PubMedCrossRefGoogle Scholar
  51. 51.
    Oflazoglu, E., I. J. Stone, et al. (2008). “Potent anticarcinoma activity of the humanized anti-CD70 antibody h1F6 conjugated to the tubulin inhibitor auristatin via an uncleavable linker.” Clin Cancer Res 14(19): 6171–80.PubMedCrossRefGoogle Scholar
  52. 52.
    Smith, L. M., A. Nesterova, et al. (2006). “Potent cytotoxicity of an auristatin-containing antibody-drug conjugate targeting melanoma cells expressing melanotransferrin/p97.” Mol Cancer Ther 5(6): 1474–82.PubMedCrossRefGoogle Scholar
  53. 53.
    Smith, L. M., A. Nesterova, et al. (2008). “CD133/prominin-1 is a potential therapeutic target for antibody-drug conjugates in hepatocellular and gastric cancers.” Br J Cancer 99(1): 100–9.PubMedCrossRefGoogle Scholar
  54. 54.
    John, B., B. R. Herrin, et al. (2003). “The B cell coreceptor CD22 associates with AP50, a clathrin-coated pit adapter protein, via tyrosine-dependent interaction.” J Immunol 170(7): 3534–43.PubMedGoogle Scholar
  55. 55.
    Walter, R. B., B. W. Raden, et al. (2008). “ITIM-dependent endocytosis of CD33-related Siglecs: role of intracellular domain, tyrosine phosphorylation, and the tyrosine phosphatases, Shp1 and Shp2.” J Leukoc Biol 83(1): 200–11.PubMedCrossRefGoogle Scholar
  56. 56.
    Ingle, G. S., P. Chan, et al. (2008). “High CD21 expression inhibits internalization of anti-CD19 antibodies and cytotoxicity of an anti-CD19-drug conjugate.” Br J Haematol 140(1): 46–58.PubMedGoogle Scholar
  57. 57.
    Press, M. F., C. Cordon-Cardo, et al. (1990). “Expression of the HER-2/neu proto-oncogene in normal human adult and fetal tissues.” Oncogene 5(7): 953–62.PubMedGoogle Scholar
  58. 58.
    Craig, F. E., K. A. Foon (2008). “Flow cytometric immunophenotyping for hematologic neoplasms.” Blood 111(8): 3941–67.PubMedCrossRefGoogle Scholar
  59. 59.
    Das, S., Y. Hahn, et al. (2008). “Topology of NGEP, a prostate-specific cell:cell junction protein widely expressed in many cancers of different grade level.” Cancer Res 68(15): 6306–12.PubMedCrossRefGoogle Scholar
  60. 60.
    DeGeorge, J. J., C. H. Ahn, et al. (1998). “Regulatory considerations for preclinical development of anticancer drugs.” Cancer Chemother Pharmacol 41(3): 173–85.PubMedCrossRefGoogle Scholar
  61. 61.
    Chanan-Khan, A. A., S. Jagannath, N. C. Munshi, R. L. Schlossman, K. C. Anderson, K. Lee, D. DePaolo, K. C. Miller, S. Zildjian, R. J. Fram, A. Qui (2007). “Phase I study of huN901-DM1 (BB-10901) in patients with relapsed and relapsed/refractory CD56-positive multiple myeloma.” ASH Annual Meeting Abstracts, Part 1 110: 1174.Google Scholar
  62. 62.
    McCann J., F. Fossella, M.A. Villalona-Calero, A.W. Tolcher, P. Fidias , R. Raju , S. Zildjian, R. Guild, R. Fram (2007). “Phase II trial of huN901-DM1 in patients with relapsed small cell lung cancer (SCLC) and CD56-positive small cell carcinoma.” American Society of Clinical Oncology Annual Meeting Proceedings 25: 18084.Google Scholar
  63. 63.
    Tolcher, A. W., B. Forouzesh, H. McCreery, L. Hammond, A. Patnaik, J. Lambert, H. Xie, M. Hoffee, R. Zentgraf, R. Zinner, B. Glisson, Y. Clinch, P. Barrinton, E. Rowinsky, F. Fossella (2005). “A Phase I and pharmacokinetic study of BB-10901, a maytansinoid immunoconjugate, in CD56-expressing tumors.” EORTC-NCI-AACR-2005, Molecular targets and cancer therapeutics.Google Scholar
  64. 64.
    Tolcher, A. W., L. Ochoa, et al. (2003). “Cantuzumab mertansine, a maytansinoid immunoconjugate directed to the CanAg antigen: a phase I, pharmacokinetic, and biologic correlative study.” J Clin Oncol 21(2): 211–22.PubMedCrossRefGoogle Scholar
  65. 65.
    Galsky, M. D., M. Eisenberger, et al. (2008). “Phase I trial of the prostate-specific membrane antigen-directed immunoconjugate MLN2704 in patients with progressive metastatic castration-resistant prostate cancer.” J Clin Oncol 26(13): 2147–54.PubMedCrossRefGoogle Scholar
  66. 66.
    Giles, F., R. Morariu-Zamfir, J. M. Lambert, S. Verstovsek, D. Thomas, F. Ravandi, D. Deangelo (2006). “Phase I study of AVE9633, an anti-CD33-maytansinoid immunoconjugate, administered as an intravenous infusion in patients with refractory/relapsed CD33-positive acute myeloid leukemia (AML).” American Society of Hematology Annual Meeting Proceedings.Google Scholar
  67. 67.
    Stasi, R. (2008). “Gemtuzumab ozogamicin: an anti-CD33 immunoconjugate for the treatment of acute myeloid leukaemia.” Expert Opin Biol Ther 8(4): 527–40.PubMedCrossRefGoogle Scholar
  68. 68.
    Rupp, U., E. Schoendorf-Holland, et al. (2007). “Safety and pharmacokinetics of bivatuzumab mertansine in patients with CD44v6-positive metastatic breast cancer: final results of a phase I study.” Anticancer Drugs 18(4): 477–85.PubMedCrossRefGoogle Scholar
  69. 69.
    Sauter, A., C. Kloft, et al. (2007). “Pharmacokinetics, immunogenicity and safety of bivatuzumab mertansine, a novel CD44v6-targeting immunoconjugate, in patients with squamous cell carcinoma of the head and neck.” Int J Oncol 30(4): 927–35.PubMedGoogle Scholar
  70. 70.
    Tijink, B. M., J. Buter, et al. (2006). “A phase I dose escalation study with anti-CD44v6 bivatuzumab mertansine in patients with incurable squamous cell carcinoma of the head and neck or esophagus.” Clin Cancer Res 12(20 Pt 1): 6064–72.PubMedCrossRefGoogle Scholar
  71. 71.
    Qin, A. W., J. Mastico, R. A. Lutz, R. J. O‘Keeffe, J. Zildjian, S. Mita, A. Phan, A. Tolcher. (2008). “The pharmacokinetics and pharmacodynamics of IMGN242 (huC242-DM4) in patients with CanAg-expressing solid tumors.” American Society of Clinical Oncology Annual Meeting Proceedings: 3066.Google Scholar
  72. 72.
    van der Velden, V. H., N. Boeckx, et al. (2004). “High CD33-antigen loads in peripheral blood limit the efficacy of gemtuzumab ozogamicin (Mylotarg) treatment in acute myeloid leukemia patients.” Leukemia 18(5): 983–8.PubMedCrossRefGoogle Scholar
  73. 73.
    Davies, Q., A. C. Perkins, et al. (1997). “The effect of circulating antigen on the biodistribution of the engineered human antibody hCTM01 in a nude mice model.” Eur J Nucl Med 24(2): 206–9.PubMedCrossRefGoogle Scholar
  74. 74.
    Hamann, P. R., L. M. Hinman, et al. (2005). “An anti-MUC1 antibody-calicheamicin conjugate for treatment of solid tumors. Choice of linker and overcoming drug resistance.” Bioconjug Chem 16(2): 346–53.PubMedCrossRefGoogle Scholar
  75. 75.
    Baselga, J., D. Tripathy, et al. (1996). “Phase II study of weekly intravenous recombinant humanized anti-p185HER2 monoclonal antibody in patients with HER2/neu-overexpressing metastatic breast cancer.” J Clin Oncol 14(3): 737–44.PubMedGoogle Scholar
  76. 76.
    Pegram, M. D., A. Lipton, et al. (1998). “Phase II study of receptor-enhanced chemosensitivity using recombinant humanized anti-p185HER2/neu monoclonal antibody plus cisplatin in patients with HER2/neu-overexpressing metastatic breast cancer refractory to chemotherapy treatment.” J Clin Oncol 16(8): 2659–71.PubMedGoogle Scholar
  77. 77.
    Polson, A. (2008). “Antibody-Drug Conjugates for the Treatment of Non-Hodgkin’s Lymphoma.” Drug Discovery and Development of InnovativeTherapeutics Conference.Google Scholar
  78. 78.
    Boyiadzis, M., K. A. Foon (2008). “Approved monoclonal antibodies for cancer therapy.” Expert Opin Biol Ther 8(8): 1151–8.PubMedCrossRefGoogle Scholar
  79. 79.
    Reichert, J. M. (2001). “Monoclonal antibodies in the clinic.” Nat Biotechnol 19(9): 819–22.PubMedCrossRefGoogle Scholar
  80. 80.
    Harries, M., I. Smith (2002). “The development and clinical use of trastuzumab (Herceptin).” Endocr Relat Cancer 9(2): 75–85.PubMedCrossRefGoogle Scholar
  81. 81.
    Roepstorff, K., L. Grovdal, et al. (2008). “Endocytic downregulation of ErbB receptors: mechanisms and relevance in cancer.” Histochem Cell Biol 129(5):563–78.PubMedCrossRefGoogle Scholar
  82. 82.
    Wahl, A. F., K. Klussman, et al. (2002). “The anti-CD30 monoclonal antibody SGN-30 promotes growth arrest and DNA fragmentation in vitro and affects antitumor activity in models of Hodgkin’s disease.” Cancer Res 62(13): 3736–42.PubMedGoogle Scholar
  83. 83.
    Bartlett, N. L., A. Younes, et al. (2008). “A phase 1 multidose study of SGN-30 immunotherapy in patients with refractory or recurrent CD30+ hematologic malignancies.” Blood 111(4): 1848–54.PubMedCrossRefGoogle Scholar
  84. 84.
    Grillo-Lopez, A. J. (2003). “Rituximab (Rituxan/MabThera): the first decade (1993–2003).” Expert Rev Anticancer Ther 3(6): 767–79.PubMedCrossRefGoogle Scholar
  85. 85.
    Dijoseph, J. F., M. M. Dougher, et al. (2007). “Therapeutic potential of CD22-specific antibody-targeted chemotherapy using inotuzumab ozogamicin (CMC-544) for the treatment of acute lymphoblastic leukemia.” Leukemia 21(11): 2240–5.PubMedCrossRefGoogle Scholar
  86. 86.
    Law, C. L., C. G. Cerveny, et al. (2004). “Efficient elimination of B-lineage lymphomas by anti-CD20-auristatin conjugates.” Clin Cancer Res 10(23): 7842–51.PubMedCrossRefGoogle Scholar
  87. 87.
    Dijoseph, J. F., M. M. Dougher, et al. (2007). “CD20-specific antibody-targeted chemotherapy of non-Hodgkin’s B-cell lymphoma using calicheamicin-conjugated rituximab.” Cancer Immunol Immunother 56(7): 1107–17.PubMedCrossRefGoogle Scholar
  88. 88.
    Press, O. W., A. G. Farr, et al. (1989). “Endocytosis and degradation of monoclonal antibodies targeting human B-cell malignancies.” Cancer Res 49(17): 4906–12.PubMedGoogle Scholar
  89. 89.
    Kovtun, Y. V., V. S. Goldmacher (2007). “Cell killing by antibody-drug conjugates.” Cancer Lett 255(2): 232–40.PubMedCrossRefGoogle Scholar
  90. 90.
    Coffman, K. T., M. Hu, et al. (2003). “Differential EphA2 epitope display on normal versus malignant cells.” Cancer Res 63(22): 7907–12.PubMedGoogle Scholar
  91. 91.
    Kiewlich, D., J. Zhang, et al. (2006). “Anti-EphA2 antibodies decrease EphA2 protein levels in murine CT26 colorectal and human MDA-231 breast tumors but do not inhibit tumor growth.” Neoplasia 8(1): 18–30.PubMedCrossRefGoogle Scholar
  92. 92.
    Carrigan, C., C. Zuany-Amorim, M. F. Mayo, D. J. Tavares, R. J. Lutz, A. E. Kellogg, V. Blanc, P. Vrignaud, M.-C. Bissery, G. Payne (2008). “Preclinical evaluation of SAR566658 (huDS6-DM4) in mice bearing human tumor xenografts of breast, ovarian, lung, cervical and pancreatic cancer.” EORTC Meeting Abstracts Annual Meeting: Abstract #525.Google Scholar
  93. 93.
    Hamann, P. R., L. M. Hinman, et al. (2005). “A calicheamicin conjugate with a fully humanized anti-MUC1 antibody shows potent antitumor effects in breast and ovarian tumor xenografts.” Bioconjug Chem 16(2): 354–60.PubMedCrossRefGoogle Scholar
  94. 94.
    Hinman, L. M., P. R. Hamann, et al. (1993). “Preparation and characterization of monoclonal antibody conjugates of the calicheamicins: a novel and potent family of antitumor antibiotics.” Cancer Res 53(14): 3336–42.PubMedGoogle Scholar
  95. 95.
    Mayo, M. F., A. P. Leung, L. Wang, P. Wunderli, G. Payne, H. Xie, R. J. Lutz (2008). “In vivo stability in mice of SAR566658 (huDS6-DM4), an immunoconjugate targeting solid tumors.” EORTC-NCI-AACR Proceedings 2008: Abstract #533.Google Scholar
  96. 96.
    Chen, Y., S. Clark, et al. (2007). “Armed antibodies targeting the mucin repeats of the ovarian cancer antigen, MUC16, are highly efficacious in animal tumor models.” Cancer Res 67(10): 4924–32.PubMedCrossRefGoogle Scholar
  97. 97.
    Junutula, J. R., H. Raab, et al. (2008). “Site-specific conjugation of a cytotoxic drug to an antibody improves the therapeutic index.” Nat Biotechnol 26(8): 925–32.PubMedCrossRefGoogle Scholar
  98. 98.
    Boghaert, E. R., L. Sridharan, et al. (2004). “Antibody-targeted chemotherapy with the calicheamicin conjugate hu3S193-N-acetyl gamma calicheamicin dimethyl hydrazide targets Lewisy and eliminates Lewisy-positive human carcinoma cells and xenografts.” Clin Cancer Res 10(13): 4538–49.PubMedCrossRefGoogle Scholar
  99. 99.
    Henry, M. D., S. Wen, et al. (2004). “A prostate-specific membrane antigen-targeted monoclonal antibody-chemotherapeutic conjugate designed for the treatment of prostate cancer.” Cancer Res 64(21): 7995–8001.PubMedCrossRefGoogle Scholar
  100. 100.
    Ma, D., C. E. Hopf, et al. (2006). “Potent antitumor activity of an auristatin-conjugated, fully human monoclonal antibody to prostate-specific membrane antigen.” Clin Cancer Res 12(8): 2591–6.PubMedCrossRefGoogle Scholar
  101. 101.
    Pan, C., J. Terrett, et al. (2008). “Human antibody conjugates of potential utility for prostate cancer therapy: a comparison of MGBA conjugates with antibodies targeting a cell surface target (prostate-specific membrane antigen) and an extracellular matrix target (Mindin/RG-1).” AACR Meeting Abstracts 2008 (Apr.2008): 4062.Google Scholar
  102. 102.
    Ross, S., S. D. Spencer, et al. (2002). “Prostate stem cell antigen as therapy target: tissue expression and in vivo efficacy of an immunoconjugate.” Cancer Res 62(9): 2546–53.PubMedGoogle Scholar
  103. 103.
    Tassone, P., V. S. Goldmacher, et al. (2004). “Cytotoxic activity of the maytansinoid immunoconjugate B-B4-DM1 against CD138+ multiple myeloma cells.” Blood 104(12): 3688–96.PubMedCrossRefGoogle Scholar
  104. 104.
    Afar, D. E., V. Bhaskar, et al. (2004). “Preclinical validation of anti-TMEFF2-auristatin E-conjugated antibodies in the treatment of prostate cancer.” Mol Cancer Ther 3(8): 921–32.PubMedGoogle Scholar
  105. 105.
    Tse, K. F., M. Jeffers, et al. (2006). “CR011, a fully human monoclonal antibody-auristatin E conjugate, for the treatment of melanoma.” Clin Cancer Res 12(4): 1373–82.PubMedCrossRefGoogle Scholar
  106. 106.
    Boghaert, E. R., L. Sridharan, et al. (2008). “The oncofetal protein, 5T4, is a suitable target for antibody-guided anti-cancer chemotherapy with calicheamicin.” Int J Oncol 32(1): 221–34.PubMedGoogle Scholar
  107. 107.
    Tassone, P., A. Gozzini, et al. (2004). “In vitro and in vivo activity of the maytansinoid immunoconjugate huN901-N2'-deacetyl-N2'-(3-mercapto-1-oxopropyl)-maytansine against CD56+ multiple myeloma cells.” Cancer Res 64(13): 4629–36.PubMedCrossRefGoogle Scholar
  108. 108.
    Chen, Q., H. J. Millar, et al. (2007). “Alphav integrin-targeted immunoconjugates regress established human tumors in xenograft models.” Clin Cancer Res 13(12): 3689–95.PubMedCrossRefGoogle Scholar
  109. 109.
    Terrett, J., L. Li-Sheng, V. Devasthali, D. King, M. Huber, C. Rao-Naik, S. Gangwar, V. Guerlavais, A. Zhang, B. Sufi, L. Chen, P. Cardarelli, J. Phillips, B. Chen, H. Huang, D. Yao, M. Coccia (2008). “Preclinical development of anti B7-H4 therapeutic antibodies.” AACR Meeting Abstracts 2008 (Apr.2008): 4986.Google Scholar
  110. 110.
    Lode, H. N., R. A. Reisfeld, et al. (1998). “Targeted therapy with a novel enediyene antibiotic calicheamicin theta(I)1 effectively suppresses growth and dissemination of liver metastases in a syngeneic model of murine neuroblastoma.” Cancer Res 58(14): 2925–8.PubMedGoogle Scholar
  111. 111.
    Aboukameel, A., A. S. Goustin, R. Mohammad, C. Zuany-Amorim, M.-C. Bissery, A. M. Al-Katib (2007). “Superior anti-tumor activity of the CD19-directed immunotoxin, SAR3419 to rituximab in non-Hodgkin’s xenograft animal models: preclinical evaluation.” ASH Annual Meeting Abstracts 2007 110: Abstract #2339.Google Scholar
  112. 112.
    Gerber, H.-P., M. Kung-Sutherland, I. Stone, C. Morris-Tilden, J. Miyamoto, R. McCormick, S. Alley, N. Okeley, B. Hayes, F. J. Hernandez-Ilizaliturri, D. Benjamin, I. S. Grewal (2008). “Potent antitumor activity of the anti-CD19 auristatin antibody-drug conjugate SGN-19A in rituximab sensitive and resistant lymphomas.” EORTC Meeting Abstracts: Abstract #507.Google Scholar
  113. 113.
    DiJoseph, J. F., D. C. Armellino, et al. (2004). “Antibody-targeted chemotherapy with CMC-544: a CD22-targeted immunoconjugate of calicheamicin for the treatment of B-lymphoid malignancies.” Blood 103(5): 1807–14.PubMedCrossRefGoogle Scholar
  114. 114.
    DiJoseph, J. F., M. E. Goad, et al. (2004). “Potent and specific antitumor efficacy of CMC-544, a CD22-targeted immunoconjugate of calicheamicin, against systemically disseminated B-cell lymphoma.” Clin Cancer Res 10(24): 8620–9.PubMedCrossRefGoogle Scholar
  115. 115.
    Hamann, P. R., L. M. Hinman, et al. (2002). “An anti-CD33 antibody-calicheamicin conjugate for treatment of acute myeloid leukemia. Choice of linker.” Bioconjug Chem 13(1): 40–6.PubMedCrossRefGoogle Scholar
  116. 116.
    Hamann, P. R., L. M. Hinman, et al. (2002). “Gemtuzumab ozogamicin, a potent and selective anti-CD33 antibody-calicheamicin conjugate for treatment of acute myeloid leukemia.” Bioconjug Chem 13(1): 47–58.PubMedCrossRefGoogle Scholar
  117. 117.
    Polson, A. G., S. F. Yu, et al. (2007). “Antibody-drug conjugates targeted to CD79 for the treatment of non-Hodgkin lymphoma.” Blood 110(2): 616–23.PubMedCrossRefGoogle Scholar
  118. 118.
    Mao, W., E. Luis, et al. (2004). “EphB2 as a therapeutic antibody drug target for the treatment of colorectal cancer.” Cancer Res 64(3): 781–8.PubMedCrossRefGoogle Scholar
  119. 119.
    Ryan, M. C., M. Hering, et al. (2007). “Antibody targeting of B-cell maturation antigen on malignant plasma cells.” Mol Cancer Ther 6(11): 3009–18.PubMedCrossRefGoogle Scholar
  120. 120.
    Kim, K. M., C. F. McDonagh, et al. (2008). “Anti-CD30 diabody-drug conjugates with potent antitumor activity.” Mol Cancer Ther 7(8): 2486–97.PubMedCrossRefGoogle Scholar
  121. 121.
    Bianco, C., H. B. Adkins, et al. (2002). “Cripto-1 activates nodal- and ALK4-dependent and -independent signaling pathways in mammary epithelial Cells.” Mol Cell Biol 22(8): 2586–97.PubMedCrossRefGoogle Scholar
  122. 122.
    Shani, G., W. H. Fischer, et al. (2008). “GRP78 and Cripto form a complex at the cell surface and collaborate to inhibit transforming growth factor beta signaling and enhance cell growth.” Mol Cell Biol 28(2): 666–77.PubMedCrossRefGoogle Scholar
  123. 123.
    Cardarelli, P., D. King, et al. (2008). “Efficacy and safety of a human anti-CD70 antibody-MGBA conjugate.” AACR Meeting Abstracts 2008 (Apr.2008): 4061.Google Scholar
  124. 124.
    King, D., J. Terrett, et al. (2008). “Mechanism of activation of a human anti-cd70 antibody-mgba conjugate and efficacy in a nude rat model of renal carcinoma.” AACR Meeting Abstracts 2008 (Apr. 2008): 4057.Google Scholar
  125. 125.
    Law, C. L., K. A. Gordon, et al. (2006). “Lymphocyte activation antigen CD70 expressed by renal cell carcinoma is a potential therapeutic target for anti-CD70 antibody-drug conjugates.” Cancer Res 66(4): 2328–37.PubMedCrossRefGoogle Scholar
  126. 126.
    McDonagh, C. F., K. M. Kim, et al. (2008). “Engineered anti-CD70 antibody-drug conjugate with increased therapeutic index.” Mol Cancer Ther 7(9): 2913–23.PubMedCrossRefGoogle Scholar
  127. 127.
    Jain, R. K. (2005). “Normalization of tumor vasculature: an emerging concept in antiangiogenic therapy.” Science 307(5706): 58–62.PubMedCrossRefGoogle Scholar
  128. 128.
    Schliemann, C., D. Neri (2007). “Antibody-based targeting of the tumor vasculature.” Biochim Biophys Acta 1776(2): 175–92.PubMedGoogle Scholar
  129. 129.
    Hanahan, D., R. A. Weinberg (2000). “The hallmarks of cancer.” Cell 100(1): 57–70.PubMedCrossRefGoogle Scholar
  130. 130.
    Mahadevan, D., D. D. Von Hoff (2007). “Tumor-stroma interactions in pancreatic ductal adenocarcinoma.” Mol Cancer Ther 6(4): 1186–97.PubMedCrossRefGoogle Scholar
  131. 131.
    Vater, C. A., C. Manning , H. Millar, F. McCabe, Q. Chen, G. M. Anderson, R. Steeves, K. Lai, R. J. Lutz (2008). Anti-tumor efficacy of the integrin-targeted immunoconjugate IMGN388 in preclinical models. EORTC-NCI-AACR-2008, Molecular targets and cancer therapeutics, Geneva, Switzerland.Google Scholar
  132. 132.
    Ostermann, E., P. Garin-Chesa, et al. (2008). “Effective immunoconjugate therapy in cancer models targeting a serine protease of tumor fibroblasts.” Clin Cancer Res 14(14): 4584–92.PubMedCrossRefGoogle Scholar
  133. 133.
    Terrett J. A., Devasthali V., C. Pan, S. Gangwar, D. King, L. Lu, P. Cardarelli, O. Cortez, C. Ching, R. Dai, C. Rao-Naik, M. Huber, S. Pogue, R. Lee, D. Passmore, H. Huang, V. Rangan, A. Zhang, B. Sufi, V. Guerlavais, L. Chen (2008). “Ptk7 as a direct and tumor stroma target in multiple solid malignancies.” 99th Annual Meeting of the American Association for Cancer Research: Abstract #1526.Google Scholar
  134. 134.
    Namkoong, H., S. M. Shin, et al. (2006). “The bone morphogenetic protein antagonist gremlin 1 is overexpressed in human cancers and interacts with YWHAH protein.” BMC Cancer 6: 74.PubMedCrossRefGoogle Scholar
  135. 135.
    Piccirillo, S. G., B. A. Reynolds, et al. (2006). “Bone morphogenetic proteins inhibit the tumorigenic potential of human brain tumour-initiating cells.” Nature 444(7120): 761–5.PubMedCrossRefGoogle Scholar
  136. 136.
    Sneddon, J. B., H. H. Zhen, et al. (2006). “Bone morphogenetic protein antagonist gremlin 1 is widely expressed by cancer-associated stromal cells and can promote tumor cell proliferation.” Proc Natl Acad Sci U S A 103(40): 14842–7.PubMedCrossRefGoogle Scholar
  137. 137.
    Stabile, H., S. Mitola, et al. (2007). “Bone morphogenic protein antagonist Drm/gremlin is a novel proangiogenic factor.” Blood 109(5): 1834–40.PubMedCrossRefGoogle Scholar
  138. 138.
    Boman, B. M., M. S. Wicha (2008). “Cancer stem cells: a step toward the cure.” J Clin Oncol 26(17): 2795–9.PubMedCrossRefGoogle Scholar
  139. 139.
    Okamoto, O. K., J. F. Perez (2008). “Targeting cancer stem cells with monoclonal antibodies: a new perspective in cancer therapy and diagnosis.” Expert Rev Mol Diagn 8(4): 387–93.PubMedCrossRefGoogle Scholar
  140. 140.
    Bonnet, D., J. E. Dick (1997). “Human acute myeloid leukemia is organized as a hierarchy that originates from a primitive hematopoietic cell.” Nat Med 3(7): 730–7.PubMedCrossRefGoogle Scholar
  141. 141.
    Clarke, M. F., J. E. Dick, et al. (2006). “Cancer stem cells – perspectives on current status and future directions: AACR Workshop on cancer stem cells.“ Cancer Res 66(19): 9339–44.PubMedCrossRefGoogle Scholar
  142. 142.
    Gil, J., A. Stembalska, et al. (2008). “Cancer stem cells: the theory and perspectives in cancer therapy.” J Appl Genet 49(2): 193–9.PubMedCrossRefGoogle Scholar
  143. 143.
    Jones, R. J., W. H. Matsui, et al. (2004). “Cancer stem cells: are we missing the target?” J Natl Cancer Inst 96(8): 583–5.PubMedCrossRefGoogle Scholar
  144. 144.
    Bao, S., Q. Wu, et al. (2006). “Glioma stem cells promote radioresistance by preferential activation of the DNA damage response.” Nature 444(7120): 756–60.PubMedCrossRefGoogle Scholar
  145. 145.
    Bao, S., Q. Wu, et al. (2006). “Stem cell-like glioma cells promote tumor angiogenesis through vascular endothelial growth factor.” Cancer Res 66(16): 7843–8.PubMedCrossRefGoogle Scholar
  146. 146.
    Dylla, S. J., L. Beviglia, et al. (2008). “Colorectal cancer stem cells are enriched in xenogeneic tumors following chemotherapy.” PLoS ONE 3(6): e2428.PubMedCrossRefGoogle Scholar
  147. 147.
    Eyler, C. E., J. N. Rich (2008). “Survival of the fittest: cancer stem cells in therapeutic resistance and angiogenesis.” J Clin Oncol 26(17): 2839–45.PubMedCrossRefGoogle Scholar
  148. 148.
    Hosen, N., C. Y. Park, et al. (2007). “CD96 is a leukemic stem cell-specific marker in human acute myeloid leukemia.” Proc Natl Acad Sci U S A 104(26): 11008–13.PubMedCrossRefGoogle Scholar
  149. 149.
    Jin, L., K. J. Hope, et al. (2006). “Targeting of CD44 eradicates human acute myeloid leukemic stem cells.” Nat Med 12(10): 1167–74.PubMedCrossRefGoogle Scholar
  150. 150.
    Kohler, G., C. Milstein (1975). “Continuous cultures of fused cells secreting antibody of predefined specificity.” Nature 256(5517): 495–7.PubMedCrossRefGoogle Scholar
  151. 151.
    Hwang, W. Y., J. Foote (2005). “Immunogenicity of engineered antibodies.” Methods 36(1): 3–10.PubMedCrossRefGoogle Scholar
  152. 152.
    Jones, P. T., P. H. Dear, et al. (1986). “Replacing the complementarity-determining regions in a human antibody with those from a mouse.” Nature 321(6069): 522–5.PubMedCrossRefGoogle Scholar
  153. 153.
    Roguska, M. A., J. T. Pedersen, et al. (1996). “A comparison of two murine monoclonal antibodies humanized by CDR-grafting and variable domain resurfacing.” Protein Eng 9(10): 895–904.PubMedCrossRefGoogle Scholar
  154. 154.
    Roguska, M. A., J. T. Pedersen, et al. (1994). “Humanization of murine monoclonal antibodies through variable domain resurfacing.” Proc Natl Acad Sci U S A 91(3): 969–73.PubMedCrossRefGoogle Scholar
  155. 155.
    Hoogenboom, H. R (2005). “Selecting and screening recombinant antibody libraries.” Nat Biotechnol 23(9): 1105–16.PubMedCrossRefGoogle Scholar
  156. 156.
    Lonberg, N (2008). “Fully human antibodies from transgenic mouse and phage display platforms.” Curr Opin Immunol 20(4): 450–9.PubMedCrossRefGoogle Scholar
  157. 157.
    Kim, S. J., Y. Park, et al. (2005). “Antibody engineering for the development of therapeutic antibodies.” Mol Cells 20(1): 17–29.PubMedGoogle Scholar
  158. 158.
    Mascelli, M. A., H. Zhou, et al. (2007). “Molecular, biologic, and pharmacokinetic properties of monoclonal antibodies: impact of these parameters on early clinical development.” J Clin Pharmacol 47(5): 553–65.PubMedCrossRefGoogle Scholar
  159. 159.
    Sedlacek, H. H., Seemann, D., Hoffmann, D., et al. (1992). Antibodies as carriers of cytotoxicity.Contributions to Oncology. G. Riethmuller, H. Koprowski, S. von Kleist. (eds.) Basel, Switzerland, Karger: 43: 29–97.Google Scholar
  160. 160.
    Adams, G. P., R. Schier, et al. (2001). “High affinity restricts the localization and tumor penetration of single-chain fv antibody molecules.” Cancer Res 61(12): 4750–5.PubMedGoogle Scholar
  161. 161.
    Fujimori, K., D. G. Covell, et al. (1990). “A modeling analysis of monoclonal antibody percolation through tumors: a binding-site barrier.” J Nucl Med 31(7): 1191–8.PubMedGoogle Scholar
  162. 162.
    Jefferis, R. (2007). “Antibody therapeutics: isotype and glycoform selection.” Expert Opin Biol Ther 7(9): 1401–13.PubMedCrossRefGoogle Scholar
  163. 163.
    Wang, S. Y., G. Weiner (2008). “Complement and cellular cytotoxicity in antibody therapy of cancer.” Expert Opin Biol Ther 8(6): 759–68.PubMedCrossRefGoogle Scholar
  164. 164.
    Desjarlais, J. R., G. A. Lazar, et al. (2007). “Optimizing engagement of the immune system by anti-tumor antibodies: an engineer’s perspective.” Drug Discov Today 12(21–22): 898–910.PubMedGoogle Scholar
  165. 165.
    Strome, S. E., E. A. Sausville, et al. (2007). “A mechanistic perspective of monoclonal antibodies in cancer therapy beyond target-related effects.” Oncologist 12(9): 1084–95.PubMedCrossRefGoogle Scholar
  166. 166.
    Salfeld, J. G. (2007). “Isotype selection in antibody engineering.” Nat Biotechnol 25(12): 1369–72.PubMedCrossRefGoogle Scholar
  167. 167.
    van der Neut Kolfschoten, M., J. Schuurman, et al. (2007). “Anti-inflammatory activity of human IgG4 antibodies by dynamic Fab arm exchange.” Science 317(5844): 1554–7.PubMedCrossRefGoogle Scholar
  168. 168.
    Yoo, E. M., L. A. Wims, et al. (2003). “Human IgG2 can form covalent dimers.” J Immunol 170(6): 3134–8.PubMedGoogle Scholar
  169. 169.
    Cartron, G., L. Dacheux, et al. (2002). “Therapeutic activity of humanized anti-CD20 monoclonal antibody and polymorphism in IgG Fc receptor FcgammaRIIIa gene.” Blood 99(3): 754–8.PubMedCrossRefGoogle Scholar
  170. 170.
    Musolino, A., N. Naldi, et al. (2008). “Immunoglobulin G fragment C receptor polymorphisms and clinical efficacy of trastuzumab-based therapy in patients with HER-2/neu-positive metastatic breast cancer.” J Clin Oncol 26(11): 1789–96.PubMedCrossRefGoogle Scholar
  171. 171.
    Weng, W. K., R. Levy (2003). “Two immunoglobulin G fragment C receptor polymorphisms independently predict response to rituximab in patients with follicular lymphoma.” J Clin Oncol 21(21): 3940–7.PubMedCrossRefGoogle Scholar
  172. 172.
    Zhang, W., M. Gordon, et al. (2007). “FCGR2A and FCGR3A polymorphisms associated with clinical outcome of epidermal growth factor receptor expressing metastatic colorectal cancer patients treated with single-agent cetuximab.” J Clin Oncol 25(24): 3712–8.PubMedCrossRefGoogle Scholar
  173. 173.
    Lazar, G. A., W. Dang, et al. (2006). “Engineered antibody Fc variants with enhanced effector function.” Proc Natl Acad Sci U S A 103(11): 4005–10.PubMedCrossRefGoogle Scholar
  174. 174.
    Schuster, M., P. Umana, et al. (2005). “Improved effector functions of a therapeutic monoclonal Lewis Y-specific antibody by glycoform engineering.” Cancer Res 65(17): 7934–41.PubMedGoogle Scholar
  175. 175.
    Shields, R. L., J. Lai, et al. (2002). “Lack of fucose on human IgG1 N-linked oligosaccharide improves binding to human Fcgamma RIII and antibody-dependent cellular toxicity.” J Biol Chem 277(30): 26733–40.PubMedCrossRefGoogle Scholar
  176. 176.
    Shinkawa, T., K. Nakamura, et al. (2003). “The absence of fucose but not the presence of galactose or bisecting N-acetylglucosamine of human IgG1 complex-type oligosaccharides shows the critical role of enhancing antibody-dependent cellular cytotoxicity.” J Biol Chem 278(5): 3466–73.PubMedCrossRefGoogle Scholar
  177. 177.
    Roopenian, D. C., S. Akilesh (2007). “FcRn: the neonatal Fc receptor comes of age.” Nat Rev Immunol 7(9): 715–25.PubMedCrossRefGoogle Scholar
  178. 178.
    DiJoseph, J. F., M. M. Dougher, et al. (2006). “Antitumor efficacy of a combination of CMC-544 (inotuzumab ozogamicin), a CD22-targeted cytotoxic immunoconjugate of calicheamicin, and rituximab against non-Hodgkin’s B-cell lymphoma.” Clin Cancer Res 12(1): 242–9.PubMedCrossRefGoogle Scholar
  179. 179.
    Jordan, M. A., L. Wilson (2004). “Microtubules as a target for anticancer drugs.” Nat Rev Cancer 4(4): 253–65.PubMedCrossRefGoogle Scholar
  180. 180.
    Lopus, M., E. Oroudjev, et al. (2008). “Maytansine derivatives and metabolites of antibody-maytansinoid conjugates inhibit microtubule polymerization and strongly suppress microtubule dynamics.” AACR Meeting Abstracts 2008 (Apr.2008): 1406.Google Scholar
  181. 181.
    Oroudjev, E., M. Lopus, et al. (2008). “Antibody-maytansinoid conjugates affect microtubule morphology and suppress microtubule dynamics in live cells.” AACR Meeting Abstracts 2008 (Apr.2008): 1403.Google Scholar
  182. 182.
    Cassady, J. M., K. K. Chan, et al. (2004). “Recent developments in the maytansinoid antitumor agents.” Chem Pharm Bull (Tokyo) 52(1): 1–26.PubMedCrossRefGoogle Scholar
  183. 183.
    Yu, T. W., L. Bai, et al. (2002). “The biosynthetic gene cluster of the maytansinoid antitumor agent ansamitocin from Actinosynnema pretiosum.” Proc Natl Acad Sci U S A 99(12): 7968–73.PubMedCrossRefGoogle Scholar
  184. 184.
    Drewinko, B., M. Patchen, et al. (1981). “Differential killing efficacy of twenty antitumor drugs on proliferating and nonproliferating human tumor cells.” Cancer Res 41(6): 2328–33.PubMedGoogle Scholar
  185. 185.
    Chabner, B. A., A. S. Levine, et al. (1978). “Initial clinical trials of maytansine, an antitumor plant alkaloid.” Cancer Treat Rep 62(3): 429–33.PubMedGoogle Scholar
  186. 186.
    Ravry, M. J., G. A. Omura, et al. (1985). “Phase II evaluation of maytansine (NSC 153858) in advanced cancer. A Southeastern Cancer Study Group trial.” Am J Clin Oncol 8(2): 148–50.PubMedCrossRefGoogle Scholar
  187. 187.
    Widdison, W. C., S. D. Wilhelm, et al. (2006). “Semisynthetic maytansine analogues for the targeted treatment of cancer.” J Med Chem 49(14): 4392–408.PubMedCrossRefGoogle Scholar
  188. 188.
    Murphy, M., S. Phinney, et al. (2008). “Immunohistochemical analysis of the glycotope targeted by huC242-DM4 indicates strong expression in several tumor types with unmet medical need.” AACR Meeting Abstracts 2008 (Apr.2008): 4898.Google Scholar
  189. 189.
    Stephan, J. P., P. Chan, et al. (2008). “Anti-CD22-MCC-DM1 and MC-MMAF conjugates: impact of assay format on pharmacokinetic parameters determination.” Bioconjug Chem 19(8): 1673–83.PubMedCrossRefGoogle Scholar
  190. 190.
    Bai, R., G. R. Pettit, et al. (1990). “Dolastatin 10, a powerful cytostatic peptide derived from a marine animal. Inhibition of tubulin polymerization mediated through the vinca alkaloid binding domain.” Biochem Pharmacol 39(12): 1941–9.PubMedCrossRefGoogle Scholar
  191. 191.
    Erickson, H. K., P. U. Park, et al. (2006). “Antibody-maytansinoid conjugates are activated in targeted cancer cells by lysosomal degradation and linker-dependent intracellular processing.” Cancer Res 66(8): 4426–33.PubMedCrossRefGoogle Scholar
  192. 192.
    Grewal, I. S. (2008). “CD70 as a therapeutic target in human malignancies.” Expert Opin Ther Targets 12(3): 341–51.PubMedCrossRefGoogle Scholar
  193. 193.
    Alley, S. C., D. R. Benjamin, et al. (2008). “Contribution of linker stability to the activities of anticancer immunoconjugates.” Bioconjug Chem 19(3): 759–65.PubMedCrossRefGoogle Scholar
  194. 194.
    Wang, L., G. Amphlett, et al. (2005). “Structural characterization of the maytansinoid-monoclonal antibody immunoconjugate, huN901-DM1, by mass spectrometry.” Protein Sci 14(9): 2436–46.PubMedCrossRefGoogle Scholar
  195. 195.
    Shields, R. L., A. K. Namenuk, et al. (2001). “High resolution mapping of the binding site on human IgG1 for Fc gamma RI, Fc gamma RII, Fc gamma RIII, and FcRn and design of IgG1 variants with improved binding to the Fc gamma R.” J Biol Chem 276(9): 6591–604.PubMedCrossRefGoogle Scholar
  196. 196.
    Hamblett, K. J., P. D. Senter, et al. (2004). “Effects of drug loading on the antitumor activity of a monoclonal antibody drug conjugate.” Clin Cancer Res 10(20): 7063–70.PubMedCrossRefGoogle Scholar
  197. 197.
    McDonagh, C. F., E. Turcott, et al. (2006). “Engineered antibody-drug conjugates with defined sites and stoichiometries of drug attachment.” Protein Eng Des Sel 19(7): 299–307.PubMedCrossRefGoogle Scholar
  198. 198.
    Wu, G., Y. Z. Fang, et al. (2004). “Glutathione metabolism and its implications for health.” J Nutr 134(3): 489–92.PubMedGoogle Scholar
  199. 199.
    Appenzeller-Herzog, C., L. Ellgaard (2008). “The human PDI family: versatility packed into a single fold.” Biochim Biophys Acta 1783(4): 535–48.PubMedCrossRefGoogle Scholar
  200. 200.
    Ciechanover, A. (2006). “Intracellular protein degradation: from a vague idea thru the lysosome and the ubiquitin-proteasome system and onto human diseases and drug targeting.” Hematology Am Soc Hematol Educ Program: 1–12, 505–6.Google Scholar
  201. 201.
    Dowell, J. A., J. Korth-Bradley, et al. (2001). “Pharmacokinetics of gemtuzumab ozogamicin, an antibody-targeted chemotherapy agent for the treatment of patients with acute myeloid leukemia in first relapse.” J Clin Pharmacol 41(11): 1206–14.PubMedCrossRefGoogle Scholar
  202. 202.
    Lutz, R. J., H. Xie, et al. (2005). “HuC242-DM4, an antibody-maytansinoid conjugate with superior preclinical activity in human CanAg-positive tumor xenograft models in SCID mice.” AACR Meeting Abstracts 2005(1): 334–c-335.Google Scholar
  203. 203.
    Erickson, H., S. Wilhelm, et al. (2008). “Evaluation of the cytotoxic potencies of the major maytansinoid metabolites of antibody maytansinoid conjugates detected in vitro and in preclinical mouse models.” AACR Meeting Abstracts 2008 (Apr.2008): 2150.Google Scholar
  204. 204.
    Francisco, J. A., C. G. Cerveny, et al. (2003). “cAC10-vcMMAE, an anti-CD30-monomethyl auristatin E conjugate with potent and selective antitumor activity.” Blood 102(4): 1458–65.PubMedCrossRefGoogle Scholar
  205. 205.
    Sanderson, R. J., M. A. Hering, et al. (2005). “In vivo drug-linker stability of an anti-CD30 dipeptide-linked auristatin immunoconjugate.” Clin Cancer Res 11(2 Pt 1): 843–52.PubMedGoogle Scholar
  206. 206.
    Doronina, S. O., T. D. Bovee, et al. (2008). “Novel peptide linkers for highly potent antibody-auristatin conjugate.” Bioconjug Chem 19(10): 1960–3.PubMedCrossRefGoogle Scholar
  207. 207.
    Linenberger, M. L., T. Hong, et al. (2001). “Multidrug-resistance phenotype and clinical responses to gemtuzumab ozogamicin.” Blood 98(4): 988–94.PubMedCrossRefGoogle Scholar
  208. 208.
    Walter, R. B., B. W. Raden, et al. (2003). “Multidrug resistance protein attenuates gemtuzumab ozogamicin-induced cytotoxicity in acute myeloid leukemia cells.” Blood 102(4): 1466–73.PubMedCrossRefGoogle Scholar
  209. 209.
    Gottesman, M. M., I. Pastan (1988). “The multidrug transporter, a double-edged sword.” J Biol Chem 263(25): 12163–6.PubMedGoogle Scholar
  210. 210.
    Leonard, G. D., T. Fojo, et al. (2003). “The role of ABC transporters in clinical practice.” Oncologist 8(5): 411–24.PubMedCrossRefGoogle Scholar
  211. 211.
    Takara, K., T. Sakaeda, et al. (2006). “An update on overcoming MDR1-mediated multidrug resistance in cancer chemotherapy.” Curr Pharm Des 12(3): 273–86.PubMedCrossRefGoogle Scholar
  212. 212.
    Sharom, F. J. (2008). “ABC multidrug transporters: structure, function and role in chemoresistance.” Pharmacogenomics 9(1): 105–27.PubMedCrossRefGoogle Scholar
  213. 213.
    Guillemard, V., H. Uri Saragovi (2004). “Prodrug chemotherapeutics bypass p-glycoprotein resistance and kill tumors in vivo with high efficacy and target-dependent selectivity.” Oncogene 23(20): 3613–21.PubMedCrossRefGoogle Scholar
  214. 214.
    Kovtun, Y., C. Audette, E. Maloney, M. Mayo, J. Jones, H. Doherty, H. Erickson, S. Wilhelm, R. Singh, G. Goldmacher, R. Chari (2008). “Novel antibody-maytansinoid conjugates with improved efficacy against multidrug-resistant tumors.” EORTC Proceedings: Abstract #518.Google Scholar
  215. 215.
    Mita, M. M., D. A. Ricart, A. C. Mita, A. Patnalk, J. Sarantopoulos, K. Sankhala, R. J. Fram, A. Qin, J. Watermill, A. W. Tolcher (2007). A phase I study of a CanAg-targeted immunoconjugate, huC242-DM4, in patients with CanAg-expressing solid tumors. J. Clin Oncol 2007 ASCO Annual Meeting Proceedings 25: 3062.Google Scholar
  216. 216.
    Tolcher A. W., A. Ricart, J. Rodon, A. Patnaik, A. Mita, M. Mita, S. Saratopolous, S. Zildjian, J. Watermill, R. J. Fram (2005). “A Phase I study of huC242-DM4 to assess the safety and pharmacokinetics of huC242-DM4 administered as a single intravenous infusion once every three weeks to subjects with solid tumors.” EORTC-NCI-AACR-2005, Molecular targets and cancer therapeutics, Philadelphia, PA 212: Abstract #212.Google Scholar
  217. 217.
    Jensen, M., F. Berthold (2007). “Targeting the neural cell adhesion molecule in cancer.” Cancer Lett 258(1): 9–21.PubMedCrossRefGoogle Scholar
  218. 218.
    Whiteman, K. R., M. F. Murphy, K. P. Cohane, W. Sun, C. N. Carrigan, M. F. Mayo, Y. Li, R. J. Lutz (2008). “Preclinical evaluation of IMGN901 (huN901-DM1) as a potential therapeutic for ovarian cancer.” American Association of Clinical Research Annual Meeting: Abstract #2135.Google Scholar
  219. 219.
    Hwu, P., M. Sznol, A. Pavlick, H. Kluger, L. Rink, K. B. Kim, N. Papadopoulos, D. Sanders, P. Bossberg, C. E. Ool, O. Hamid (2008). “A Phase I/II study of CRO-11-vcMMAE, an antibody-drug conjugate, in patients with unresectable stage III or stage IV melanoma.” American Society for Clinical Oncology Annual Meeting Proceedings: 9029.Google Scholar
  220. 220.
    Oflazoglu, E., K. M. Kissler, et al. (2008). “Combination of the anti-CD30-auristatin-E antibody-drug conjugate (SGN-35) with chemotherapy improves antitumour activity in Hodgkin lymphoma.” Br J Haematol 142(1): 69–73.PubMedCrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC 2010

Authors and Affiliations

  • Carol A. Vater
    • 1
  • Victor S. Goldmacher
    • 1
  1. 1.ImmunoGen, Inc.WalthamUSA

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